Polycythemia vera (PV) is the most common myeloproliferative disorder. Relevance of this project to the[unreadable] public health is that elucidation of molecular PV defect will result in specific therapy and eventual cure of PV.[unreadable] Based on our previous studies, we hypothesize that PV is caused by changes in gene expression at several[unreadable] levels. Identification of our finding of the chromosome 9p uniparenteral disomy was reproduced and provided[unreadable] the basis for the recent discovery of the constitutively active mutant JAK2 V617F on chromosome 9p that is[unreadable] present in the majority of PV patients: JAK2 is mutated in a single allele and it is converted to homozygosity[unreadable] by uniparenteral disomy in approximately 30% of PV patients. However, the JAK2 V617F alteration does not fully explain[unreadable] the pathophysiology of PV.[unreadable] 1) We hypothesize that other genetic events are needed for the development of the full PV phenotype. In[unreadable] these studies we will pursue a) identification of positional candidates through familial co-segregation of[unreadable] genomic regions with the PV phenotype. b) identification of positional candidates by shared regions of[unreadable] genome architecture or expression changes, c) we will guide our genomic analyses by using the fund of[unreadable] knowledge about JAK2, its pathways and interacting proteins, and analyzing those PV patients without JAK2[unreadable] V617F mutation.[unreadable] 2) a) We will study the cellular and biochemical effect of JAK2 V617F in cell lines and correlate these with[unreadable] the effect of tyrosine kinase inhibitors; similar studies will be done in polycythemic mice with JAK2 V617F in[unreadable] hematopoietic cells, b) We will correlate the PV clinical response (an ongoing clinical study of imatinib[unreadable] mesylate with Dr. Verstorvsek - see project 6) to imatinib mesylate with their JAK2 V617F genotype and[unreadable] expression, c) We will attempt to identify the pathophysiology of PV in those patients who respond to imatinib[unreadable] mesylate.